Pressure-sensitive adhesive and patch employing the same

ABSTRACT

An adhesive which comprises aqueous and nonaqueous polymers suitable for holding an lipophilic drug, etc., and has tackiness and cohesiveness which are sufficient for the plaster of a patch; and a patch employing the adhesive. The adhesive contains a polymer which comprises one or more kinds of acrylic or methacrylic monomer units, at least one kind of the monomer units having a hydroxy group, and which has been crosslinked with a boron compound.

TECHNICAL FIELD

The present invention relates to an adhesive that is affixed to thesurface of skin so as to continuously administer a drug into a livingbody through the skin, and a patch employing same.

BACKGROUND ART

An adhesive layer constituting a patch normally comprises a mixturecontaining a drug and, as a main component, a polymer, and with regardto means for improving the tackiness and cohesiveness of this mixture,various techniques have been carried out in which a crosslinked polymeris formed by adding an appropriate crosslinking agent during theformulation process so as to gel the adhesive layer. Such an adhesivecan be obtained by a method in which a drug, etc. is added to acrosslinked polymer, but in order to add a sufficient amount of drug tothe adhesive layer and solve problems in molding, a method in which anappropriate crosslinking agent is added during the formulation processto a mixture containing a drug and, as a main component, a polymer so asto gel the mixture is widely employed.

Since many of the drugs used in patches are lipophilic, various types oflipophilic acrylic polymers containing substantially no water are usedas the polymer constituting the adhesive layer. In recent years inparticular, this type of nonaqueous patch often contains a liquidsubstance as a component to improve the permeability of the drug, butthis further degrades the tackiness and cohesiveness of the adhesivelayer, and crosslinking of the polymer is therefore a very importantobject.

Crosslinking of the polymer is generally carried out by a reactionbetween an appropriate crosslinking agent and a crosslinking functionalgroup of the polymer. Representative examples of the crosslinkingfunctional group include a carboxyl group, an amino group, and a hydroxygroup. Thereamong, since a hydroxy group has low reactivity comparedwith a carboxyl group or an amino group, there might in general be lessirritation of the skin such as reddening or edema caused by residualfunctional groups, and it might be thought that those with a hydroxygroup would be suitable for application in a patch, which needs to beaffixed to the skin for a long period of time.

With regard to a crosslinking agent for a hydroxy group-containingpolymer, Japanese Patent No. 2967788 proposes the use of a metalchelate, a metal alcoholate, etc., but since the metal chelate and themetal alcoholate are generally highly reactive, they might decompose ordenature the drug during a crosslinking reaction, and skin irritation ormore serious symptoms might be caused by residual crosslinking agent.

On the other hand, an aqueous gel is conventionally formed using, forexample, a borate, a silicate, or a salt of a polyvalent metal such ascalcium or magnesium, which crosslinks with a hydroxy group-containingpolymer under mild reaction conditions. However, these inorganiccompounds have not so far been used for the preparation of a nonaqueousgel because of problems during the preparation such as the inorganiccompounds generally having poor solubility in organic solvents.

An object of the present invention is therefore to solve the problems ofthe prior art and provide an adhesive and a patch employing same, theadhesive having sufficient tackiness and cohesiveness as the plaster ofa patch and being produced from an aqueous or nonaqueous polymer that issuitable for containing an lipophilic drug, etc.

In the present description, ‘nonaqueous polymer’ means a polymeremploying, as a solvent for the polymer, an organic solvent or a mixedsolvent containing an organic solvent as a main component, and ‘aqueouspolymer’ means a polymer employing, as a solvent for the polymer, wateror a mixed solvent containing water as a main component.

DISCLOSURE OF INVENTION

As a result of an intensive investigation by the present inventors inorder to solve the above-mentioned problems, it has been found that, byusing as a crosslinking agent a boron-containing compound, which hasconventionally been used for formation of an aqueous gel of a polyvinylalcohol, an adhesive having sufficient tackiness and cohesiveness can beobtained from a polymer having a hydroxy group in its molecule,regardless of whether it is aqueous or nonaqueous and even when it isnot a polyvinyl alcohol, and as a result of a further investigation thepresent invention has been accomplished.

That is, the present invention relates to an adhesive comprising apolymer containing one or more kinds of acrylic or methacrylic monomerunit, at least one of the kinds of monomer unit having a hydroxy group,and the polymer being crosslinked by a boron-containing compound.

Furthermore, the present invention relates to the adhesive wherein theboron-containing compound is boric acid or a boric acid derivative.

Moreover, the present invention relates to the adhesive wherein itcontains substantially no water.

Furthermore, the present invention relates to the adhesive wherein itcontains a liquid component that is compatible with the polymer.

Moreover, the present invention relates to a patch comprising theadhesive.

Furthermore, the present invention relates to the patch wherein theadhesive contains a drug.

Moreover, the present invention relates to the patch wherein it containssubstantially no water.

In the present description, ‘containing substantially no water’ meansthat no water is used in the production of the adhesive or the patch, orthat the adhesive or the patch that is produced contains no water.

Since the boron-containing compound as a crosslinking agent in thepresent invention is soluble in a hydrophilic organic solvent at asufficient concentration, it can crosslink a polymer containingsubstantially no water, thus giving sufficient tackifying power andcohesive power, and thereby enabling desirable physical properties as apatch containing an lipophilic drug, a liquid component, etc. to beachieved.

MODES FOR CARRYING OUT THE INVENTION

The composition and form of the adhesive of the present invention areexplained.

The crosslinkable monomer unit of the polymer contained in the adhesiveof the present invention is not particularly limited as long as the unithas at least one hydroxy group.

Specific examples thereof include hydroxy group-containing acrylicmonomer units such as 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylateand 4-hydroxybutyl acrylate, hydroxy group-containing methacrylicmonomer units such as 2-hydroxyethyl methacrylate, 3-hydroxypropylmethacrylate and 4-hydroxybutyl methacrylate, and monomer units such asvinyl alcohol, allyl alcohol, 3-buten-1-ol and 3-buten-2-ol. Among theseexamples, the hydroxy group-containing acrylic monomer units and thehydroxy group-containing methacrylic monomer units are preferable.2-Hydroxyethyl acrylate is particularly preferable.

These hydroxy group-containing monomer units can be used singly or in acombination of two or more kinds.

In the present invention, either an aqueous polymer or a nonaqueouspolymer can be used, and when the nonaqueous polymer is used, an acrylicpolymer or a methacrylic polymer is preferably used.

The acrylic and methacrylic polymers used in the present invention arenot particularly limited, and specific examples include those having asa monomer unit acrylic acid, methacrylic acid, acrylonitrile, acrylicand methacrylic acid straight-chain alkyl esters such as methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl and tridecyl esters, branched alkyl esters such as 2-ethylhexylester, and substituted alkyl esters such as 2-hydroxyethyl,3-hydroxypropyl and 4-hydroxybutyl esters. One or more kinds of thesemonomers can be used in addition to the hydroxy group-containing monomerin the adhesive of the present invention.

It is preferable for the acrylic monomer or the methacrylic monomer tobe the main component in the polymer contained in the adhesive, and theacrylic monomer or methacrylic monomer is contained at at least 30 wt %relative to the polymer, preferably 50 to 90 wt %, and particularlypreferably 70 to 90 wt %.

The polymer contained in the adhesive of the present invention maycontain, in addition to the hydroxy group-containing monomer and theacrylic or methacrylic monomer, one or more kinds of other monomers.Specific examples of such monomers include vinyl acetate,N-vinyl-2-pyrrolidone, itaconic acid, maleic acid, allylamine, styrene,reactive polymers (macro monomers), vinyl propionate,methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpiperazine,vinylpyrazine, vinylpyrrole, vinylimidazole, vinylcaprolactam,vinyloxazole, vinylmorpholine, 2-ethylhexyl acrylate, vinylpyrrolidone,methoxyethyl acrylate and acrylic acid. 2-Ethylhexyl acrylate andvinylpyrrolidone are particularly preferable.

The polymer containing the above-mentioned monomer components, which isused in the production of the patch of the present invention, is notparticularly limited as long as it contains a hydroxy group and at leastone kind of acrylic or methacrylic component; it may be a polymer of asingle monomer or it may be a copolymer, but a copolymer is particularlypreferable. Specific examples thereof include a copolymer of2-hydroxyethyl acrylate, 2-ethylhexyl acrylate andN-vinyl-2-pyrrolidone.

The solvent for the polymer used in production of the adhesive of thepresent invention can be either aqueous or organic as long as thepolymer can be dissolved or made into a uniform emulsion, but a lowboiling point organic solvent that can be removed by heating at 60° C.to 150° C. and that can form a nonaqueous gel is preferable, andspecific examples thereof include ethyl acetate, toluene, THF, hexane,dichloromethane, chloroform, ether, methanol and ethanol.

With regard to the boron-containing compound that can be used forcrosslinking of the polymer contained in the adhesive of the presentinvention, boric acid and derivatives thereof in which the boron is +3valent can be cited. Examples of the boric acid derivatives include aborate and a borate ester. With regard to the borate, there can be citedchemically acceptable inorganic and organic salts whose condensationnumber is not limited as long as the boron is +3 valent. Specificexamples thereof include sodium tetraborate and ammonium borate.Examples of the borate ester include methyl borate, ethyl borate, propylborate and butyl borate. Boric acid is particularly preferable. Thesecompounds can be anhydrous compounds or hydrates, but the anhydrouscompounds are preferable.

These boron-containing compounds as the crosslinking agent arepreferably added at 0.01 to 20 wt % relative to the total weight of thecomposition of the adhesive layer, and are more preferably added at 0.1to 10 wt %, and particularly preferably 0.1 to 5 wt %, while taking intoconsideration the physical properties and skin irritation of theadhesive and the preparation.

The adhesive of the present invention can contain a liquid componentthat is compatible with the polymer; such a liquid component is notparticularly limited, but an lipophilic liquid component can be cited,and it can be an absorption promoting agent, a solubilizing agent, aplasticizer, etc.

Examples of the absorption promoting agent include caprylic acid,caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid,oleic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, stearylalcohol, cetyl alcohol, methyl laurate, hexyl laurate, lauric aciddimethanolamide and isopropyl myristate.

Examples of the plasticizer include squalane, squalene, silicon oil,petroleum oil (e.g., paraffinic process oil, naphthenic process oil,aromatic process oil), and plant oil (e.g., olive oil, castor oil,camellia oil, tall oil, peanut oil).

Examples of the solubilizing agent include dipropylene glycol, glycerol,ethylene glycol and polyethylene glycol.

When the adhesive of the present invention is used in a patch, it can beintegrally molded so that the adhesive includes a substrate, or theadhesive can be formed into a sheet shape that is used as an adhesivelayer, and as necessary the patch comprises a support layer supportingthe adhesive layer and a release paper layer provided on the adhesivelayer.

The drug used in the adhesive layer comprising the adhesive of thepresent invention is not particularly limited as long as it canpercutaneously permeate a biological membrane. Examples of the drug usedin the present invention include general anesthetics, hypnoticsedatives, antipyretic/anti-inflammatory analgesics, steroidalanti-inflammatory agents, analeptics/stimulants, anti-motion sicknessagents, agents affecting the nervous system, local anesthetics, skeletalmuscle relaxants, agents for the autonomic nervous system,antispasmodics, anti Parkinsonism drugs, antihistamines, cardiotonics,antiarrhythmic agents, diuretics, antihypertensives, vasoconstrictors,vasodilators, agents for arteriosclerosis, respiratory stimulants,antitussive/expectorants, agents for treating peptic ulcers,cholagogues, hormonal drugs, agents for urogenital and anal organs,agents for parasitic skin disease, emollients, vitamin preparations,mineral preparations, hemostatics, anticoagulants, agents for liverdisease, agents for habitual intoxication, agents for treating gout,agents for diabetes, antineoplastic agents, radioactive drugs,traditional Chinese preparations, antibiotics, chemotherapeutics,anthelmintics and antiprotozoan agents, and narcotics.

Examples of the antipyretic/anti-inflammatory analgesics includeacetoaminophenone, phenacetin, mefenamic acid, diclofenac, fulfenamicacid, aspirin, salicylic acid, aminopyrine, alclofenac, ibuprofen,naproxen, flurbiprofen, ketoprofen, sodium amfenac, epirizole,indomethacin, pentazocine, and piroxicam; and examples of the steroidalanti-inflammatory agents include hydrocortisone, triamcinolone,dexamethasone, betamethasone, and prednisolone.

Examples of the vasodilators include diltiazem, pentaerythritol,isosorbide, trapidil, nicorandil, nitroglycerin, prenilamine,molsidomine, and tolazoline; examples of the antiarrhythmic agentsinclude procainamide, lidocaine, propranolol, alprenolol, atenolol,nadolol, metoprolol, ajmaline, disopyramide, and mexitilen; and examplesof the antihypertensives include ecarazine, indapamide, clonidine,bunitrolol, labetalol, captopril, guanabenz, mebutamate, andbethanidine.

Examples of the antitussive expectorants include carbetapentane,chloperastine, oxeladin, clobutinol, clofedanol, noscapine, ephedrine,isoproterenol, clorprenaline, methoxyphenamine, procaterol, tulobuterol,clenbuterol, and ketotifen; examples of the antineoplastic agentsinclude cyclophosphamide, fluorouracil, tegafur, mitomycin C,procarbazine, doxifluridine, and ranimustine; and examples of the localanesthetics include ethyl aminobenzoate, tetracaine, procaine,dibucaine, oxybuprocaine, ambroxol, and propitocaine.

Examples of the hormonal drugs include propylthiouracil, thiamazole,metenolone acetate, estradiol, norethisterone acetate, estriol, andprogesterone; examples of the antihistamines include diphenhydramine,chlorpheniramine, promethazine, cyproheptadine, and diphenylpyraline;examples of anticoagulants include potassium warfarin and ticlopidine;examples of the antispasmodics include methylatropine bromide andscopolamine; examples of the general anesthetics include sodiumthiopental and sodium pentobarbital; examples of hypnotic sedativesinclude bromvalerylurea, amobarbital, and phenobarbital; examples ofanti-epileptics include phenyloin; and examples of the analeptics andstimulants include methamphetamine.

Examples of the anti-motion sickness agents include difenidol andbetahistine; examples of the agents affecting the nervous system includechlorpromazine, thioridazine, meprobamate, imipramine, chlordiazepoxide,and diazepam; examples of the skeletal muscle relaxants includesuxamethonium and eperisone; examples of the agents for the autonomicnervous system include neostigmine bromide, and bethanechol chloride;examples of the anti Parkinsonism drugs include pergolide andamantadine; examples of the diuretics include hydroflumethiazide,isosorbide, and furosemide; examples of the vasoconstrictors includephenylephrine; examples of the respiratory stimulants include lobeline,dimorpholamine, and naloxone; and examples of the agents for treatingpeptic ulcers include glycopyrronium bromide, proglumide, cetraxate,cimetidine, and spizofurone.

Examples of the cholagogues include ursodeoxycholic acid and osalmid;examples of the agents for urogenital and anal organs include hexamine,sparteine, dinoprost, and ritodrine; examples of the agents forparasitic skin disease include salicylic acid, ciclopirox olamine, andcroconazole; examples of the emollients include urea; examples of thevitamin preparations include calcitriol, thiamine, sodium riboflavinphosphate, pyridoxine, nicotinamide, panthenol, and ascorbic acid; andexamples of the hemostatics include ethamsylate.

Examples of the agents for liver disease include tiopronin; examples ofthe agents for habitual intoxication include cyanamide; examples of theagents for treating gout include colchicine, probenecid, andsulfinpyrazone; examples of the agents for diabetes include tolbutamide,chlorpropamide, sodium glymidine, glybuzole, buformin, and insulin;examples of the antibiotics include benzylpenicillin, propicillin,cloxacillin, ampicillin, bacampicillin, carbenicillin, cephaloridine,cefoxitin, erythromycin, chloramphenicol, tetracycline, kanamycinsulfate, and cycloserine; examples of the chemotherapeutics includeisoniazid, pyrazinamide, and ethionamide; and examples of the narcoticsinclude morphine, codeine phosphate, cocaine, fentanyl, and pethidine.

These drugs can be used singly or in a combination of two or more types,and any form of the drugs such as an inorganic salt or an organic saltcan of course be included. The amount of drug added is 0.1 to 30 wt %relative to the total weight of the composition of the adhesive layerwhile taking into consideration a sufficient permeation rate for thepatch, irritation of the skin such as reddening, etc.

The adhesive layer of the patch of the present invention can contain anabsorption promoting agent; the absorption promoting agent that can beused here can be any compound that is conventionally recognized to havea skin absorption promoting effect, and examples thereof include fattyacids, fatty alcohols, fatty acid esters, and ethers having 6 to 20carbons, aromatic organic acids, aromatic alcohols, aromatic organicacid esters and ethers (those above can be either saturated orunsaturated, and can be cyclic, straight chain, or branched) and,furthermore, lactate esters, acetate esters, monoterpenoid compounds,Azone (trade name), Azone derivatives, glycerol fatty acid esters,sorbitan fatty acid esters (Span (trade name) series) polysorbate types(Tween (trade name) series), polyethylene glycol fatty acid esters,polyoxyethylene hardened castor oil types (HCO series), and sugar fattyacid esters.

Specifically, preferred examples include caprylic acid, capric acid,caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid,oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristylalcohol, oleyl alcohol, cetyl alcohol, methyl laurate, isopropylmyristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate,salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamicacid, methyl cinnamate, cresol, cetyl lactate, ethyl lactate, propyllactate, geraniol, thymol, eugenol, terpineol, 1-menthol, borneol,d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerolmonolaurate, sucrose monolaurate, polysorbate 20, propylene glycol,dipropylene glycol, polyethylene glycol monolaurate, polyethylene glycolmonostearate, HCO-60, and 1-[2-(decylthio)ethyl] azacyclopentan-2-one(hereinafter called ‘pyrrothiodecane’), and particularly preferredexamples include lauryl alcohol, 1-menthol, propylene glycol,pyrrothiodecane, dipropylene glycol, and isopropyl myristate.

Such absorption promoting agents can be added at 0.01 to 60 wt %, morepreferably 0.1 to 40 wt %, and particularly preferably 0.1 to 20 wt %,relative to the total weight of the composition of the adhesive layer,while taking into consideration adequate penetrability as a patch andirritation of the skin such as reddening or edema.

Moreover, as necessary, an antioxidant, a preservative, anultraviolet-absorbing agent, and an anti-crystallizing agent can beused, and preferred examples of the antioxidant include tocopherol andester derivatives thereof, ascorbic acid, ascorbic acid stearic acidester, nordihydroguaiaretic acid, dibutyl hydroxytoluene (BHT), andbutyl hydroxyanisole. Preferred examples of the preservative includeethyl paraoxybenzoate, propyl paraoxybenzoate, and butylparaoxybenzoate. Preferred examples of the ultraviolet-absorbing agentinclude p-aminobenzoic acid derivatives, anthranilic acid derivatives,salicylic acid derivatives, coumarin derivatives, amino acid compounds,imidazoline derivatives, pyrimidine derivatives, and dioxanederivatives. As the anti-crystallizing agent, polyvinyl pyrrolidone,etc. is preferable. The total amount of such antioxidant, preservative,ultraviolet-absorbing agent, and anti-crystallizing agent can preferablybe 15 wt % or less, and more preferably 10 wt % or less, relative to thetotal weight of the composition of the adhesive layer of the patch.

A adhesive layer having the above-mentioned composition can be producedby any method. For example, a drug-containing base composition is meltedby heating, applied on a release paper or a support, and then laminatedto a support or a release paper to give the present preparation.Alternatively, a drug-containing base component is dissolved in asolvent such as toluene, hexane, or ethyl acetate and spread on arelease paper or a support, and after the solvent is removed by drying,the drug-containing base component is laminated to a support or arelease paper to give the present preparation. Furthermore, with regardto the patch of the present invention, as long as the adhesive layercomprising the adhesive has the above-mentioned composition containing aboron-containing compound and a drug, any other kinds of configurationand starting materials for the components can be used.

For example, the patch of the present invention can comprise, inaddition to the above-mentioned adhesive layer, a support layer forsupporting the adhesive layer and a release paper layer provided on theadhesive layer. A stretchable or non-stretchable support can be employedas the support layer. For example, it can be selected from fabrics,nonwoven fabrics, polyurethane, polyester, polyvinyl acetate,polyvinylidene chloride, polyethylene, polyethylene terephthalate,aluminum sheet, and composite materials thereof.

The present invention is explained below in further detail withreference to Examples of the present invention, but the presentinvention is not limited to these Examples and can be modified in avariety of ways without departing from the scope and spirit of thepresent invention. In the Examples, ‘%’ means wt % in all cases.

EXAMPLE 1

DURO-TAK ® (No. 387-2287) 4.45 g  89% Ethyl acetate solution (solidsconc.: 50%) Isopropyl myristate 0.5 g (solids)  10% Boric acid [methanolsolution 0.05 g  1% (30 mg/mL)] Total 5.0 g 100%

In the above composition, the DURO-TAK® (No. 387-2287, manufactured byNational Starch and Chemical Company), which is an acrylic polymer, andisopropyl myristate were mixed, 2 mL of ethyl acetate was added thereto,the mixture was stirred for 1 hour, the boric acid solution was thenadded thereto, and the mixture was stirred for 5 minutes to give anadhesive layer solution. This was spread out on a silicone-treatedsurface of an 80 μm thick polyethylene terephthalate (PET) film andcrosslinked at 100° C. for 15 minutes to give an 80 μm adhesive layer.As a support, a 30 μm thick sand-matted PET film was laminated so thatthe sand-matted surface was in contact with the adhesive layer, thusgiving a matrix preparation of the present invention. After thepreparation thus obtained was stored at 65° C. for 48 hours, theadhesive power was measured using a probe tack tester, and it was foundthat it was 102 gF, which is good. When a 25+test piece was cut out andaffixed to an upper arm and peeled off 2 hours later, there was noresidue of the adhesive on the skin. These results suggest that thepreparation obtained using the adhesive of the present invention has theperformance of a patch that has appropriate tackiness and cohesivepower.

EXAMPLE 2

DURO-TAK ® (No. 387-2287) 2.9 g (solids)  58% Estradiol 0.2 g  4%Norethisterone acetate 0.35 g  7% Isopropyl myristate 0.5 g  10%Polyvinylpyrrolidone 1.0 g  20% Boric acid [methanol solution 0.05 g  1%(30 mg/mL)] Total 5.0 g 100%

In the above composition, the estradiol, norethisterone acetate,isopropyl myristate, and polyvinylpyrrolidone were mixed, 2 mL ofethanol was added thereto, the mixture was stirred for 2 hours, theDURO-TAK® and 2 mL of ethyl acetate were then added thereto anddissolved therein, and the mixture was further stirred for 3 hours untila uniform solution was obtained. The boric acid solution was addedthereto and stirred for 5 minutes to give an adhesive layer solution.This was spread out in the same manner as in Example 1, and a supportlayer was laminated to give a matrix preparation of the presentinvention. After the preparation thus obtained was stored at 65° C. for48 hours, the adhesive power of the preparation was measured using aprobe tack tester, and it was found that it was 267 gF, which is good.When a 25φ test piece was cut out and affixed to an upper arm and peeledoff 30 minutes later, there was no residue of the adhesive on the skin.The actual measurements of the drug concentrations of this preparationwere 100.7% and 100.4% with respect to the initial concentrations ofestradiol and norethisterone acetate, suggesting that there wassubstantially no decomposition of the drugs during the crosslinkingreaction. Furthermore, when the stability of this preparation at 40° C.was examined, the concentrations of estradiol and norethisterone acetateafter one month were 99.8% and 100.4% respectively relative to theinitial concentrations, which are good results.

COMPARATIVE EXAMPLE 1

DURO-TAK ® (No. 387-2287) 4.5 g (solids)  90% Isopropyl myristate 0.5 g 10% Total 5.0 g 100%

The above-mentioned composition was mixed and stirred for 1 hour to givean adhesive layer solution. A matrix preparation was obtained in thesame manner as in Example 1 except that no boric acid solution wasadded. After the preparation thus obtained was stored at 65° C. for 48hours, when a 25φ test piece was cut out and affixed to an upper arm andpeeled off 2 hours later, there was residue of the adhesive on the skin.

COMPARATIVE EXAMPLE 2

DURO-TAK ® (No. 387-2287) 2.95 g (solids)  59% Estradiol 0.2 g  4%Norethisterone acetate 0.35 g  7% Isopropyl myristate 0.5 g  10%Polyvinylpyrrolidone 1.0 g  20% Total 5.0 g 100%

In the above composition, the estradiol, norethisterone acetate,isopropyl myristate, and polyvinylpyrrolidone were mixed, 2 mL ofethanol was added thereto, the mixture was stirred for 2 hours, theDURO-TAK® and 2 mL of ethyl acetate were then added thereto, and themixture was further stirred for 3 hours to give an adhesive layersolution. A matrix preparation was obtained in the same manner as inExample 2 except that no boric acid solution was added. After thepreparation thus obtained was stored at 65° C. for 48 hours, when a25+test piece was cut out and affixed to an upper arm and peeled off 30minutes later, there was residue of the adhesive on the skin.

Adhesive Power Test

The adhesive power was measured as follows.

-   Measurement method: a 1 cm square test piece was cut out of each    patch, and a tack value was measured under the conditions below    using a probe tack tester (No. 1216S) manufactured by Rigaku Kogyo.-   Probe: Bakelite-   Adhesion time: 1 sec-   Peel speed: 1 mm/sec-   Load weight: 200 g    Drug Content Test

The drug content was measured as follows.

Measurement method: after a 25φ test piece was cut out of each patch,the release paper was removed, the total weight of the adhesive layerand the support was measured, this was placed in a 50 mL centrifugetube, 40 mL of an acetonitrile solution and a 10 mL of a 0.05%acetonitrile solution of benzophenone as an internal standard were addedthereto, and the mixture was subjected to ultrasonic extraction for 60minutes. 0.1 mL of the extract was filtered using a membrane filter andthen diluted with 0.9 mL of acetonitrile, and the drug contents of eachpreparation were calculated from area ratios of estradiol,norethisterone acetate, and the internal standard using high performanceliquid chromatography. The preparation from which the drug had beenextracted was taken out, the adhesive layer was removed from the supportand dried, the weight of the support was measured, the weight of theadhesive layer was calculated, and the drug concentrations werecalculated from these weights and the content of each drug.

INDUSTRIAL APPLICABILITY

A patch employing the adhesive of the present invention includes anadhesive that is formed from an aqueous or nonaqueous polymer suitablefor holding an lipophilic drug, etc., and is a useful patch havingsufficient tackiness and cohesiveness.

1. An adhesive comprising a polymer containing one or more kinds ofacrylic or methacrylic monomer unit, at least one of the kinds ofmonomer unit having a hydroxy group, and the polymer being crosslinkedby a boron-containing compound.
 2. The adhesive according to claim 1,wherein the boron-containing compound is boric acid or a boric acidderivative.
 3. The adhesive according to claim 1, said adhesivecontaining substantially no water.
 4. The adhesive according to claim 1,said adhesive containing a liquid component that is compatible with thepolymer.
 5. A patch comprising the adhesive according to claim
 1. 6. Thepatch according to claim 5, wherein the adhesive contains at least onedrug.
 7. The patch according to claim 5, wherein the adhesive containssubstantially no water.